2-222201034-TACACACACAC-TACACAC

Variant names:

• chr2-222201034-TACAC-T
• rs373626774
• NM_181458.4:c.*370_*373delGTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_181458.4(PAX3):​c.*370_*373delGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000991 in 797,472 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (5 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 4 publications found

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 Gene-Disease associations (from GenCC):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000911 (136/149354) while in subpopulation SAS AF = 0.00385 (18/4678). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.*370_*373delGTGT		3_prime_UTR_variant	Exon 9 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.*370_*373delGTGT		3_prime_UTR_variant	Exon 9 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.000911 AC: 136 AN: 149260 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00384

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.000974

GnomAD4 exome AF: 0.00101 AC: 654 AN: 648118 Hom.: 5 AF XY: 0.00113 AC XY: 379 AN XY: 335284

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00290 AC: 49 AN: 16878

American (AMR) AF: 0.000997 AC: 29 AN: 29092

Ashkenazi Jewish (ASJ) AF: 0.000486 AC: 8 AN: 16476

East Asian (EAS) AF: 0.000202 AC: 6 AN: 29642

South Asian (SAS) AF: 0.00414 AC: 212 AN: 51242

European-Finnish (FIN) AF: 0.000107 AC: 4 AN: 37422

Middle Eastern (MID) AF: 0.00256 AC: 10 AN: 3904

European-Non Finnish (NFE) AF: 0.000682 AC: 294 AN: 431378

Other (OTH) AF: 0.00131 AC: 42 AN: 32084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000911 AC: 136 AN: 149354 Hom.: 0 Cov.: 31 AF XY: 0.000893 AC XY: 65 AN XY: 72814

African (AFR) AF: 0.00222 AC: 91 AN: 40924

American (AMR) AF: 0.000935 AC: 14 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00385 AC: 18 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67056

Other (OTH) AF: 0.000964 AC: 2 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373626774; hg19: chr2-223065753;